2. Academic Validation
  3. Design, synthesis and biological evaluation of indole-2-carboxylic acid derivatives as IDO1/TDO dual inhibitors

Design, synthesis and biological evaluation of indole-2-carboxylic acid derivatives as IDO1/TDO dual inhibitors

  • Eur J Med Chem. 2020 Feb 15:188:111985. doi: 10.1016/j.ejmech.2019.111985.
Guonan Cui 1,  Fangfang Lai 2,  Xiaoyu Wang 1,  Xiaoguang Chen 3,  Bailing Xu 4
Affiliations

Affiliations

  • 1 Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences&Peking Union Medical College, Beijing, 100050, China.
  • 2 State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences&Peking Union Medical College, Beijing, 100050, China.
  • 3 State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences&Peking Union Medical College, Beijing, 100050, China. Electronic address: [email protected].
  • 4 Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences&Peking Union Medical College, Beijing, 100050, China. Electronic address: [email protected].
PMID: 31881488 DOI: 10.1016/j.ejmech.2019.111985
Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are involved in the key steps of tryptophan metabolism and are potential new targets for tumor immunotherapy. In this work, a variety of indole-2-carboxylic acid derivatives were synthesized, and their inhibitory activities against both Enzymes along with structure-activity relationships were investigated. As a result, a number of 6-acetamido-indole-2-carboxylic acid derivatives were found to be potent dual inhibitors with IC50 values at low micromolar levels. Among them, compound 9o-1 was the most potent inhibitor with an IC50 value of 1.17 μM for IDO1, and 1.55 μM for TDO, respectively. In addition, a para-benzoquinone derivative 9p-O, resulted from the oxidation of compound 9p, was also identified and it showed strong inhibition against the two Enzymes with IC50 values at the double digit nanomolar level. Using molecular docking and molecular dynamic simulations, we predicted the binding modes of this class of compounds within IDO1 and TDO binding pocket. The results provide insights for further structural optimization of this series of IDO1/TDO dual inhibitors.

Keywords

Dual inhibitors; Indole-2-carboxylic acid; Indoleamine 2,3-dioxygenase 1; Tryptophan 2,3-dioxygenase.

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